Forkhead Transcription Factor FOXO1 is a Direct Target of Progestin to Inhibit Endometrial Epithelial Cell Growth
Forkhead Transcription Factor FOXO1 is a Direct Target of Progestin to Inhibit Endometrial Epithelial Cell Growth
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DOI：
10.1158/1078-0432.ccr-10-1287
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发表时间：
2011-02-01
影响因子：
11.5
通讯作者：
Inoue, Masaki
中科院分区：
文献类型：
--
作者：
Kyo, Satoru;Sakaguchi, Junko;Inoue, Masaki
目的和实验设计：尽管黄体酮在侵袭性和侵袭前子宫内膜肿瘤中的治疗作用，但其对子宫内膜上皮生长的抑制作用的分子机制在很大程度上是未知的。本研究的目的是利用最初建立的表达孕酮受体的永生化和转化子宫内膜上皮细胞系的体外和体内处理模型，阐明黄体酮对子宫内膜上皮细胞作用的分子机制。结果：在该模型中，黄体酮能有效抑制细胞生长，诱导G0/G1阻滞而非凋亡，不诱导p21/WAF-1。通过DNA微阵列分析，我们确定了24个基因，其表达在黄体酮治疗后增加了10倍以上。在这些基因中，我们特别关注了叉头盒转录因子FOXO1，它被认为是子宫内膜去个体化的关键基因。黄体酮在体外和体内均显著诱导FOXO1基因表达，主要在细胞核内表达。这种诱导不是由于FOXO1通过蛋白去磷酸化而典型激活，而是由于FOXO1启动子激活和mRNA诱导。siRNA抑制FOXO1显著减弱黄体酮对子宫内膜上皮细胞生长的抑制作用。通过引入Akt的显性负性形式破坏Akt的活性，增加了细胞核FOXO1的积累，增强了黄体酮的作用。结论：FOXO1是黄体酮的直接靶点，提示黄体酮根除子宫内膜瘤变的分子机制。临床癌症研究；17 (3);525 - 37。(c) 2010年aacr。
Purpose and experimental design: Despite the therapeutic utility of progestin in invasive and preinvasive endometrial neoplasias, the molecular mechanisms through which it exerts inhibitory effects on endometrial epithelial growth are largely unknown. The aim of the study was to clarify the molecular mechanisms of progestin action to endometrial epithelial cells using originally established in vitro and in vivo treatment models for immortalized and transformed endometrial epithelial cell lines that express progesterone receptor.Results: In this model, progestin effectively inhibited the cell growth, inducing G0/G1 arrest rather than apoptosis without p21/WAF-1 induction. Using DNA microarray analysis, we identified 24 genes whose expression increased more than 10-fold on progestin treatment. Of these genes, we paid special attention to forkhead box transcription factor FOXO1, known as a key gene for endometrial decidualization. Progestin markedly induced FOXO1 gene expression mainly in the nuclei in vitro and in vivo. This induction was not due to the canonical activation of FOXO1 via protein dephosphorylation but due to FOXO1 promoter activation and mRNA induction. siRNA inhibition of FOXO1 significantly attenuated the effects of progestin to inhibit endometrial epithelial cell growth. Disrupting Akt activity by the introduction of the dominant negative form of Akt increased nuclear FOXO1 accumulation and enhanced the effect of progestin.Conclusion: These findings suggest that FOXO1 is a direct target of progestin, implicating novel molecular mechanisms of progestin to eradicate endometrial neoplasia. Clin Cancer Res; 17( 3); 525-37. (C) 2010 AACR.